An M protein coiled coil unfurls and exposes its hydrophobic core to capture LL-37

Author:

Kolesinski Piotr1ORCID,Wang Kuei-Chen1,Hirose Yujiro2ORCID,Nizet Victor2ORCID,Ghosh Partho1ORCID

Affiliation:

1. Department of Chemistry & Biochemistry, University of California, San Diego

2. Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego

Abstract

Surface-associated, coiled-coil M proteins of Streptococcus pyogenes (Strep A) disable human immunity through interaction with select proteins. However, coiled coils lack features typical of protein–protein interaction sites, and it is therefore challenging to understand how M proteins achieve specific binding, for example, with the human antimicrobial peptide LL-37, leading to its neutralization. The crystal structure of a complex of LL-37 with M87 protein, an antigenic M protein variant from a strain that is an emerging threat, revealed a novel interaction mode. The M87 coiled coil unfurled and asymmetrically exposed its hydrophobic core to capture LL-37. A single LL-37 molecule was bound by M87 in the crystal, but in solution additional LL-37 molecules were recruited, consistent with a ‘protein trap’ neutralization mechanism. The interaction mode visualized crystallographically was verified to contribute significantly to LL-37 resistance in an M87 Strep A strain and was identified to be conserved in a number of other M protein types that are prevalent in human populations. Our results provide specific detail for therapeutic inhibition of LL-37 neutralization by M proteins.

Funder

National Institutes of Health

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

Reference46 articles.

1. Towards automated crystallographic structure refinement with phenix.refine;Afonine;Acta Crystallographica. Section D, Biological Crystallography,2012

2. iMOSFLM: a new graphical interface for diffraction-image processing with MOSFLM;Battye;Acta Crystallographica. Section D, Biological Crystallography,2011

3. Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein;Buffalo;Nature Microbiology,2016

4. Improvement of molecular-replacement models with Sculptor;Bunkóczi;Acta Crystallographica. Section D, Biological Crystallography,2011

5. Determinants for the activation and autoinhibition of the diguanylate cyclase response regulator WspR;De;Journal of Molecular Biology,2009

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